LDL receptor-related protein (LRP1) is an endocytic receptor for multiple ligands, including proteases, growth factors, apolipoproteins, and extracellular matrix proteins. In some cell types, including neurons, neuron-like cells, and Schwann cells, ligand-binding to LRP1 triggers robust cell-signaling. This "direct" pathway by which LRP1 regulates cell-signaling promotes cell survival and cell migration. LRP1 also regulates the composition of the plasma membrane proteome. Although multiple mechanisms are involved, LRP1 and receptors in the same gene family facilitate the endocytosis of other plasma membrane proteins. When LRP1 regulates the abundance or trafficking of another cell-signaling receptor in the plasma membrane, activation of important cell-signaling pathways may be controlled "indirectly" by LRP1. The urokinase receptor (uPAR) was the first cell-signaling receptor identified as a member of the LRP1-regulated plasma membrane proteome. Because LRP1 down-regulates cell-surface uPAR by facilitating its endocytosis, under some conditions, uPAR-initiated cell-signaling may be inhibited by LRP1. However, the relationship between LRP1 and uPAR is complicated because uPAR endocytosis may be necessary for sustained uPAR-initiated cell-signaling. Certain cell-signaling factors, including ERK, phosphatidylinositol 3-kinase, and Rac1 are regulated by LRP1, directly, and indirectly through uPAR. Thus, the predominant effect of LRP1 on cell-signaling, in different cell types, may depend on the abundance of LRP1 and uPAR and on the availability of ligands for LRP1 and uPAR. Opportunities for targeting the uPAR-LRP1 system through drug discovery are discussed.